An inhalant is a preparation intended to be administered as a medicament from an oral cavity or nasal cavity mainly to a lower airway such as a trachea, bronchi and alveoli. A lower airway, of an airway, is defined herein as a trachea, bronchi, bronchioles, alveoli, etc.
Inhalants are expected to target organs, to act as preparations for local administration to thoracopathy such as asthma, bronchitis and pulmonary emphysema of medicaments, and to relieve side effects and realize quick efficacy on the basis of the targeting, and many of them have already been practically used. Much attention has recently been drawn to inhalants as medicaments to be generally administered to transfer physiologically active peptides, proteins, etc., from alveoli to a blood stream (V. H. L. Lee, "Peptide and Protein Drug Delivery," Marcel Dekker, 1991, pp. 1-56). Furthermore, vaccine preparations such as an influenza vaccine have also been tried to induce local immunity by inhalation of an antigen.
Such inhalants can be classified as follows according to a state of the particles depositing within an airway: (1) a solution depositing as droplets; and (2) an aerosol or powder depositing as powder. A solution is usually an aqueous solution of a medicament. It is formed into mist by a nebulizer, (or atomizer) and administered to within an airway as minute droplets, thereby depositing within the airway in the form of droplets. On the other hand, in the case of aerosol, a medicament is usually filled in a pressurized container in the form of a dispersion or solution in fluorohydrocarbon. When the aerosol is released therefrom at the time of administration, fluorohydrocarbon is gradually vaporized, and the dispersed or dissolved medicament gradually becomes a fine particle powder, which finally deposits within the airway as a fine particle powder. Moreover, in the case of a powder, a fine particle powder containing a medicament is filled as a powder in a container such as a hard capsule. A patient usually inhales it as powder mist therefrom by patient's own inspired air through a suitable medicator, and the fine particle powder itself deposits within the airway.
Desirable properties of the inhalants can be classified as follows, by aspects of medicament efficacy and by aspects of physical chemistry.
Firstly, with regard to aspects of medicament efficacy, since an airway has a complicated and narrow structure, the medicament is required to be delivered to a target site therewithin efficiently and deposited. Delivery of the medicament to target sites such as a trachea, bronchi, branchioles and alveoli and deposition thereof at the target sites require participation of many factors such as a particle size; properties of the particles, e.g., density, shape and electric charge; a concentration of the mist, a particle size distribution and respiration patterns (see, for example, V. H. L. Lee, "Peptide and Protein Drug Delivery," Marcel Dekker, 1991, p. 10 mentioned above). However, of these factors, the most important one is a particle size. Since the relationship between a particle size and a delivery site differs depending on researchers, it is not absolute. However, an example of the relationships is as follows: particles having a size of 10 .mu.m or more are trapped within on oral cavity and nasal cavity, and deposited there; they are required to have a size of approximately 5 to 15 .mu.m to be delivered to a trachea and bronchi, and deposited there; they are required to have a size of approximately 2 to 5 .mu.m to be delivered to bronchioles, and deposited there; there are required to have a size of approximately 0.3 to 2 .mu.m to be delivered to alveoli, and deposited there (report from "Workshop on Medical Aerosol").
After a comprehensive review of other reports, it may be concluded that for the purpose of efficiently delivering a medicament to a site deeper than a trachea, namely, to a lower airway and depositing it there, it desirably has a particle size in the range from 0.5 to 10 .mu.m.
Secondly, since the surface of an airway such as a trachea and bronchi is covered with a mucosa, the airway is a very sensitive organ, a preparation should therefore be non-irritative. Additives and residual solvents which may injure the mucosa should be avoided as far as possible.
Thirdly, it is desirable that a medicament is retained at a target site within the airway for a time sufficient to realize its action. An epidermis within the airway has cilia, which move in such a way that inhaled foreign materials are moved to the esophagus. Accordingly, in order to display the efficacy thereof, it is desirable that the medicament is not readily moved by cilia and retained at the site to be deposited. Sustained release of the medicament while it is retained further enhances its efficacy.
For example, in the case of a treatment for asthma, disodium cromoglycate requiring frequent administration and steroids whose dose is desired to be decreased from the standpoint of safety become significantly useful when they are formulated to sustained action preparations requiring a decreased number of administration and a decreased amount of dose. Moreover, in the case of administering a physiologically active peptide protein, a preparation thereof intended to improve mucosa-adhesivity or mucosa-staying properties is expected to be absorbed efficiently. Accordingly, designing a sustained action preparation with an inhalant may become a widely applicable useful technique.
Fourthly, it is a matter of course that an inhalant as well as other forms of medicaments is desired to be used simply. Especially, an inhalant is desired to be easily and readily used at the time of a paroxysm of asthma, etc.
Next, in view of the physicochemical aspect of an inhalant, firstly, fine particles constituting preparations are desirably uniform regardless of whether the preparations are in solution or in powder. Requirements of the particle uniformity are not only a matter of course from the standpoint of quality standards but also a necessity for surely realizing delivery and deposition of the fine particles within an airway to obtain the efficacy of the preparations. Secondly, preparations are desirably stable. Particularly in the case of medicaments used for chronic diseases such as asthma and bronchitis, preparations capable of being preserved at room temperature are desired. Thirdly, preparations should be capable of being industrially produced in good yields. The preparations should therefore be produced by a method enabling the industrial production mentioned above possible.
In view of desired properties of inhalants as described above, it is understood from examination of the forms of the above-mentioned conventional inhalants that these inhalants do not necessarily satisfy all the desired properties.
Firstly, droplets having a particle size of 0.5 to 10 .mu.m can be efficiently generated from solutions if a nebulizer of suitable performance is selected. However, a nebulizer is required to generate mist, and it can be used neither simply nor conveniently nor portably. Solutions are difficult to retain at target sites because they are aqueous, although solutions cause no problem of irritation if the additives are selected appropriately. In addition, a liposome preparation has been proposed as means for improving the retaining properties in a solution state at target sites (see Japanese Unexamined Patent Publication No. 58-128318). However, liposomes are in general unstable, and are difficult to be preserved at ordinary temperature, for example, at room temperature over a long period. It is understood from the aforementioned description that the conventional solutions are not always satisfactory.
Secondly, an aerosol utilizing fluorohydrocarbon can efficiently generate fine particles having a particle size of 0.5 to 10 .mu.m when medicament particles to be dispersed in the fluorohydrocarbon are powdered finely. Use of an aerosol is simple if a metered dose inhaler is used, and the problem of irritation scarcely occurs. Problems as to uniformity, safety and productivity seldom occur when an aerosol is used. However, control of the use of fluorohydrocarbon is demanded because of the problem of global environmental pollution. As described above, an aerosol agent utilizing fluorohydrocarbon is not always satisfactory and replacement of an aerosol agent is strongly demanded in view of environmental problems.
Thirdly, although inhalants prepared as powders have heretofore been relatively insufficiently developed, much attention has quickly been drawn thereto because of the necessity of developing a simple administration method which is free of the fluorohydrocarbon problems mentioned above and which replaces solutions. There are the following three types of conventional powders:
(1) A well-mixed powder comprising ultrafine medicament particles and excipient particles selected from lactose, etc., and having a particle size larger than that of the medicament particles, the excipient being deposited at an oral cavity, pharynx or larynx and only the ultrafine medicament particles being delivered to and deposited at a lower airway such as a trachea and bronchi when the particle mixture is administered to within an airway from a suitable container;
(2) A powder composed of medicament particles having a relatively large particle size prepared by mildly granulating ultrafine medicament particles, the granulated powder being disintegrated into the constituent ultrafine medicament particles during its flight when administered to an airway from a suitable container, the thus formed medicament ultrafine particles being delivered to and deposited at a lower airway such as a trachea and bronchi; and
(3) A powder consisting only of ultrafine medicament particles, and being delivered to and deposited at a lower airway such as a trachea and bronchi when administered to an airway from a suitable container.
These three types of powders still have unsolved problems as described below.
With regard to powders in (1) and (3), only medicament particles are deposited at target sites, and retention and sustained release thereof at the sites are difficult to ensure.
Retention and sustained medicament release at target sites of a powder in (2) is difficult to ensure, the situation being similar to that of powder in (1). Moreover, ultrafine medicament particles themselves cannot be mildly granulated in some cases due to the physical properties of the medicament itself. An amount of disintegration into the constituent ultrafine particles may sometimes differ, and as a result a delivered amount and a deposited amount at target sites may vary.
Accordingly, there is desired realization of a powder inhalant which exhibits good delivery to and good deposition at a lower airway such as a trachea and bronchi, and which is excellent in retention and medicament sustained release as deposition sites.
Microcapsules prepared from a polylactic acid, a biodegradable polymer, for such a powder inhalant have been proposed (see Japanese Unexamined Patent Publication No. 3-17014). Although sustained medicament release from the microcapsules can be expected in this method, adhesion to and retention at a lower airway mucosa of the microcapsules themselves are most difficult to ensure. Since formation of the ultrafine particles is not easy and forming the particles having a particle size of 0.5 to 10 .mu.m is very difficult, the productivity of the inhalant is low. Furthermore, the inhalant has a disadvantage that removal of the organic solvent used in microencapsulation of the inhalant is not easy.
Accordingly, there is desired realization of a powder inhalant which exhibits good delivery to and good deposition at a lower airway such as a trachea and bronchi, which is excellent in retention and medicament sustained release at deposition sites and which is also excellent in all of such properties as productivity, stability, safety and uniformity.
In addition, with regard to a pharmaceutical composition comprising a cellulose lower alkyl ether and a medicament, the present inventors have disclosed a sustained action preparation for a nasal cavity in Japanese Examined Patent Publication No. 60-7965. The ultrafine particle powder for inhalation comprising a specific cellulose lower alkyl ether and a medicament of the present invention and a preparation containing the ultrafine particle powder should be clearly distinguished from the preparation disclosed in the above-mentioned patent publication by the following respects:
(1) The invention of the patent publication relates to a preparation for a nasal cavity, whereas the present invention relates to a preparation for inhalation capable of being delivered principally to a lower airway. The particle size distributions of both preparations can be definitely distinguished from each other.
(2) There is no disclosure in the patent publication which suggests that the composition of the invention may further be pulverized to give ultrafine particles for use in inhalation.
(3) The ultrafine particles for inhalation of the present invention which are capable of being delivered principally to a lower airway differ from the composition for a nasal cavity disclosed in the above-mentioned patent publication in that the ultrafine particles cannot be produced by the method wherein a cellulose lower alkyl ether and a medicament are mixed to give a composition. A cellulose lower alkyl ether prior to mixing cannot even be ground to give particles having a particle size suitable for an inhalant. That is, medicament particles of an inhalant generally have a particle size distribution of approximately 0.5 to 10 .mu.m, and they are usually prepared by grinding using a jet mill, and the like. However, a cellulose lower alkyl ether in fine particles having a particle size less than 10 .mu.m cannot be obtained in a high yield at least by dry grinding. Even when ultrafine particles of a cellulose lower alkyl ether can be obtained, it is very difficult to obtain appropriately agglomerated fine particles which behave uniformly, by mixing the ultrafine particles with medicament ultrafine particles. The ultrafine particles for inhalation of the present invention can be produced only by spray drying.
(4) Furthermore, Japanese Examined Patent Publication No. 60-7965 discloses the use of cellulose lower alkyl ethers as bases constituting powder preparations, together with a medicament for a powder preparation for administration to nasal cavity mucosa having a particle size of 20-250 .mu.m for 90% by weight or more of the particles. Examples of such cellulose lower alkyl ethers are methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl hydroxyethyl cellulose, sodium carboxymethyl cellulose. Among these, it is disclosed that methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose are preferable in view of smell and irritation. On the other hand, according to the present invention, hydroxypropyl cellulose and hydroxypropyl methyl cellulose are selected as a component constituting a powder preparation having a particle size of 0.5-10 .mu.m for 80% by weight or more thereof. However, the reasons for the selection thereof is a completely different technical idea from those of the above-mentioned powder preparation for nasal cavity mucosa. Namely, as mentioned above, the most important property for the inhalant is a particle size thereof. Regarding this point, it is surprisingly found from the following two experiments that the hydroxypropyl cellulose and hydroxypropyl methyl cellulose according to the present invention are different from the other cellulose lower alkyl ethers (the details will be further described later as Reference Experiments).
Experiment 1: Stability of Particle Size During Storage of Fine Particle For Inhalant
According to the present method, powder (A) comprising beclometasone dipropionate and hydroxypropyl cellulose and having a particle size of 0.5-10 .mu.m for 80% by weight or more thereof, powder (B) comprising beclometasone dipropionate and hydroxypropyl methyl cellulose and having the same particle size as mentioned above, powder (C) comprising beclometasone dipropionate and methyl cellulose and having the same particle size as mentioned above, powder (D) comprising beclometasone dipropionate and hydroxyethyl cellulose and having the same particle size as mentioned above, powder (E) comprising beclometasone dipropionate and sodium carboxymethyl hydroxyethyl cellulose and having the same particle size as mentioned above and powder (F) comprising beclometasone dipropionate and sodium carboxymethyl cellulose and having the same particle size were prepared by a spray drying method.
Contrary to the above, according to the method disclosed in Japanese Examined Patent Publication No. 60-7965, mixed powder (G) of beclometasone dipropionate and hydroxypropyl cellulose having a particle size of 20-250 .mu.m for 90% by weight or more thereof, mixed powder (H) of beclometasone dipropionate and hydroxypropyl methyl cellulose having the same particle size as mentioned above, mixed powder (I) of beclometasone dipropionate and methyl cellulose having the same particle size as mentioned above, mixed powder (J) of beclometasone dipropionate and hydroxyethyl cellulose having the same particle size as mentioned above, mixed powder (K) of beclometasone dipropionate and sodium carboxymethyl hydroxyethyl cellulose having the same particle size as mentioned above and mixed powder (L) of beclometasone dipropionate and sodium carboxymethyl cellulose having the same particle size were prepared by a mechanical mixing method.
Furthermore, powder (M) to powder (R) having the combination corresponding to that of the above-mentioned powder (G) to powder (L), respectively, were prepared by a spray drying method in such a manner that the particle size of 90% by weight or more was within the same range of 20 to 250 .mu.m.
The above-mentioned powders (A)-(R) were humidified at 25.degree. C./50% R.H. for 48 hours, followed by measuring the particle sizes by a particle size distribution measuring apparatus of a laser diffraction type. Therefore, the powders were allowed to stand at 25.degree. C./65% R.H. for 7 days, followed by measuring the particle sizes by the same method. As a result, in the case of the powders (G)-(L) and (M)-(R) having the necessary particle size distribution for preparation for nasal cavity administration, no particle size changes after storage were observed, irrespective of kinds of the cellulose lower alkyl ethers. Contrary to this, in the case of the powders (A)-(F) having the necessary particle size distribution for an inhalant, the powders (A) and (B) using hydroxypropyl cellulose and hydroxypropyl methyl cellulose did not exhibit the particle size change after storage. However, in the cases of the other powders using methyl cellulose (C), hydroxyethyl cellulose (D), sodium carboxymethyl hydroxyethyl cellulose (E), and sodium carboxymethyl cellulose (F), the presence of a large size particle was observed, which was presumed by the formation of agglomerated mass of the original particles.
Experiment 2: Depositionability of Fine Particle for Inhalation within Lung
The powders (A)-(F) for an inhalant used in the above-mentioned Experiment 1 were examined, regarding the depositionability thereof within a lung under a humidified condition (i.e., 37.degree. C./98%), by a cascade impactor. As a result, the powder (A) containing hydroxypropyl cellulose and the powder (B) containing hydroxypropyl methyl cellulose according to the present invention exhibited such an average aerodynamic radius that, when these powders are actually administered to human beings, it is estimated that a sufficient amount thereof is deposited on a trachea, a primary bronchus and peripheral lung portions therefrom. However, the other powders (C) to (F) containing the other cellulose lower alkyl ethers exhibited such an average aerodynamic radius that it is estimated that these powders are deposited on a larynx. Thus, it is estimated that the powders are not possible to be deposited on the targeted portions, i.e., a trachea, a primary bronchus and peripheral lung portions therefrom.
Although it is not clear why the remarkable difference between hydroxypropyl cellulose, hydroxypropyl methyl cellulose and the other cellulose lower alkyl ethers occurs, it is estimated that this difference is related to the hygroscopicity (equilibrium moisture) of the cellulose lower alkyl ethers. It is known that the hygroscopicity of hydroxypropyl cellulose, hydroxypropyl methyl cellulose is lower than that of methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl hydroxyethyl cellulose. Nevertheless, it is not expected by those skilled in the art that the above-mentioned difference in the hygroscopicity causes the above-mentioned remarkable difference between the particle size required for the inhalant and the particle size required for the preparation for administration to nasal cavity (in which no substantial differences are observed), regarding the agglomeration or growth of the particles, shown in the above-mentioned Experiments.
As is clear from the above two Experiments, the technical idea according to the present invention finding the use of hydroxypropyl cellulose and hydroxypropylmethyl cellulose among the cellulose lower alkyl ethers and the technical idea selecting, as a preferable one, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose among the same cellulose lower alkyl ethers are completely different. Furthermore, the technical idea according to the selection of the present invention is an essential matter for the inhalant technique and exhibit the novelty and inventive step of the present invention.
From the illustration described above, it will be understood that the ultrafine particle powder for inhalation of the present invention is entirely different from the composition for a nasal cavity disclosed by Japanese Examined Patent Publication No. 60-7965.
On the other hand, it has already been known that a pharmaceutical composition comprising a cellulose lower alkyl ether and a medicament is produced by spray drying. For example, medicament particles are coated with hydroxypropyl cellulose by spray drying, whereby hydroxypropyl cellulose masks the taste of the medicament itself and controls elution thereof. M. Vidgren et el. have reported that fine particles having a particle size of approximately 3 to 10 .mu.m and comprising cromoglycate disodium or beclometasone dipropionate, and polyacrylic acid and/or sodium carboxymethyl cellulose are obtained by spray drying, and that the resultant fine particles exhibit sustained releasing properties and mucosa-adhesivity (Drug Development and Industrial Pharmacy, 18 (5), 581-597, 1992, 6th International Conference on Pharmaceutical Technology, Paris Jun. 2-4, 1992). However, production, by spry drying, of ultrafine particles comprising a specific cellulose lower alkyl ether and a medicament and having the particle distribution of the present invention has never been disclosed, and the use of the ultrafine particles of the present invention as an inhalant capable of being delivered principally to a lower airway has not even been suggested.